2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)one derivatives

ABSTRACT

This invention provides compounds of formula I,  
                 
 
     R is hydrogen or alkyl of 1-6 carbon atoms;  
     R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;  
     R 1 , R 2 , R 3 , and R 4  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;  
     X is CR 5 R 6  or a carbonyl group;  
     R 5  and R 6  are each, independently, hydrogen or alkyl of 1-6 carbon atoms;  
     or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R 1 , R 2 , R 3 , or R 4  are not hydrogen;  
     which are 5HT 2C  receptor agonists useful for the treatment of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, obesity, type II diabetes, and epilepsy.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No.09/891,593 filed on Jun. 26, 2001, which is a continuation-in-part ofU.S. application Ser. No. 09/455,220, filed on Dec. 6, 1999, whichclaims the benefit of U.S. Provisional Application No. 60/172,234, filedDec. 17, 1998.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to derivatives of2,3,4,4a-tetrahydro-1H-pyrazino[1,2,-a]quinoxalin-5(6H)ones which areserotonin 5-hydroxytryptamine 2_(C) (5HT_(2C)) receptor agonists usefulfor the treatment of disorders such as obsessive-compulsive disorder,depression, anxiety, schizophrenia, migraine, sleep disorders, eatingdisorders, obesity, type II diabetes, and epilepsy.

[0003] Obesity is a medical disorder characterized by an excess of bodyfat or adipose tissue. Comorbidities associated with obesity are Type IIdiabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke,osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers,some infertility, and early mortality. As the percentage of obeseindividuals continues to rise both in the U.S. and abroad, obesity isexpected to be a major health risk in the 21^(st) Century. The serotonin5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptorwhich is expressed in neurons in many regions of the human centralnervous system. [Wilkinson, L. O. and Dourish, C. T. in SerotoninReceptor Subtypes: Basic and Clinical Aspects (ed. Peroutka, S. J. )147-210 (Wiley-Liss, New York, 1991).] The 5HT_(2C) receptor (formerlycalled the 5HT_(1C) receptor) is a prominent subtype of the serotoninreceptor found in the central nervous system of both rats and humans. Itis expressed widely in both cortical and subcortical regions. [Julius,D. MacDermott, A. B., Axel, R. Jessell, T. M. Science 241:558-564(1988).] Studies in several animal species and in humans have shown thatthe non-selective 5HT_(2C) receptor agonist, meta-chlorophenylpiperazine(MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M. , Williams,C., Walsh, A. E. S., Fairburn, C. G. Nature 376: 557 (1995).] Tecott, etal have demonstrated that transgenic mice lacking the 5HT_(2C) receptoreat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L.M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F.,Jullus, D. Nature 374: 542-546 (1995).] Compounds of this invention are5HT_(2C) receptor subtype selective agonists which are selective overother monoamine receptors, causes a reduction in food intake and resultin a reduction in weight gain. Other therapeutic indications for5HT_(2C) agonists are obsessive compulsive disorder, depression, panicdisorder, schizophrenia, sleep disorders, eating disorders, andepilepsy.

[0004] U.S. Pat. Nos. 4,032,639; 4,089,958; and 4,203,987 describe2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6)-ones andderivatives thereof as antihypertensive agents. In contrast, compoundsof this invention bind to and activate the 5HT_(2C) receptors in the CNSand are useful for the treatment of CNS disorders.

[0005] Indian J. Chem. 17B, 244-245 (1979) discloses 3-Substituted2,3,4,4a,5,6-Hexahydro-1(H)-pyrazino[1,2-a]quinoxalines which exhibit noanorexigenic or stimulant activity at 60 mg/kg i.p. dose. Weak CNSdepressant activity and significant hypotensive activity inanaesthetized animals. Tachyphylaxis was observed.

DESCRIPTION OF THE INVENTION

[0006] This invention provides compounds of formula I having thestructure

[0007] R is hydrogen or alkyl of 1-6 carbon atoms;

[0008] R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbonatoms, or aroyl;

[0009] R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl,—CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbonatoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbonatoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7carbon atoms, or aroyl;

[0010] X is CR₅R₆ or a carbonyl group;

[0011] R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6carbon atoms;

[0012] or a pharmaceutically acceptable salt thereof, with the provisothat at least one of R₁, R₂, R₃, or R₄ are not hydrogen;

[0013] which are 5HT_(2C) receptor agonists useful for the treatment ofdisorders involving the central nervous system such asobsessive-compulsive disorder, depression, anxiety, panic disorder,schizophrenia and schizophrenic disorders, migraine, sleep disorders,eating disorders, obesity, type II diabetes, and epilepsy.

[0014] This invention provides methods for treatment, inhibition oralleviation of symptoms of schizophrenic disorders in a mammal in needof such treatment. These methods include those for the schizophrenicdisorders known in the art, including those defined by the AmericanPsychiatric Associations Diagnostic and Statistical Manual of MentalDisorders, Third Edition (DSM-III, 1980), its revision DSM-III-R (1987)or the DSM-IV (1996). These methods include those for schizophrenia,schizophreniform syndromes, or schizoaffective disorders. Also includedare related psychotic syndromes referred to as brief reactive psychoses,as well as borderline or latent schizophrenia and simple schizophrenia,which are also referred to as borderline or schizotypal personalitydisorders. Additional methods include late onset schizophrenia-likesyndromes, such as the involutional paraphrenias, which are also knownas paranoid disorder or atypical psychosis.

[0015] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereoisomers. While shown without respect to stereochemistry inFormula I, the present invention includes such optical isomers anddiastereoisomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

[0016] The term “alkyl” includes both straight- and branched-chainsaturated aliphatic hydrocarbon groups. The term “aroyl” is defined asan aryl ether, where aryl is defined as an aromatic system of 6-14carbon atoms, which may be a single ring or multiple aromatic ringsfused or linked together as such that at least one part of the fused orlinked rings forms the conjugated aromatic system. Preferred aryl groupsinclude phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl,phenanthryl groups. Halogen is defined as Cl, Br, F, and I.

[0017] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids.

[0018] Preferred compounds of this invention are those in which at leastone of R₁, R₂, R₃, or R₄ are not hydrogen, and the non-hydrogensubstituents of R₁, R₂, R₃, and R₄ are halogen or trifluoromethyl.

[0019] Preferred enantiomerically pure compounds of formulas IA and IBare provided as follows:

[0020] wherein R, R₁, R₂, R₃, and R₄ are as described above.

[0021] The compounds of this invention can be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using literature procedures.These schemes show the preparation of representative compounds of thisinvention.

[0022] In Scheme 1, the symbol Cbz represents a carbobenzyloxy group andY stands for chlorine, fluorine, or bromine. A solution of4-carbobenzyloxypiperazine-2-carboxylic acid (I) is allowed to reactwith a substituted ortho-nitrohalobenzene (II) to give a4-carbobenzyloxy-1-(o-nitro-substituted-phenyl)-piperazine-2-carboxylicacid (III). The reaction is carried out in an inert organic solvent,such as dimethylsulfoxide, in the presence of a base, such astriethylamine, at a temperature above ambient temperature, such as50-150° C.

[0023] The intermediate (III) is cyclized by a process involvingreduction of the nitro group to an amino group, preferably by reactionof a metal, such as iron, in an acid, such as acetic acid, followed byheating at elevated temperature, such as 50-100° C., to effectcyclization to (IV). Removal of the Cbz protecting group using borontribromide, catalytic reduction or a base, such as potassium hydroxide,gives products of this invention (IVa). Or treatment of (IV) with abase, such as sodium hydride, followed by reaction with an alkyl halide,such as methyl iodide, give intermediates (V). Removal of the Cbz groupwith boron tribromide or potassium hydroxide give compounds of thisinvention (VI) where R′ is lower alkyl.

[0024] Compounds (VI) can also be alkylated a second time using a base,such as sodium hydride, and an alkyl halide, such as methyl iodide, togive compounds of this invention (VIII). Alternatively, compounds (VI)can be reduced with a reducing agent, such as borane in THF, tocompounds of this invention (VII). Compounds (VIII) can also be reducedwith borane in THF to give (IX) which are compounds of this invention.

[0025] The amide of compounds (V) can also be reduced to amines (VII)using a reducing agent, such as borane in tetrahydrofuran, at 0-50° C.Compounds (VII) are also compounds of this invention.

[0026] Likewise, the amide of compounds (VI) can be reduced to amines(VIII) which are compounds of this invention. In compounds (VI) where R′is acyl this group is put on, as already described, after reduction ofamides (VI) where R′ is hydrogen.

[0027] In Scheme 2, the carboxylic acids of intermediate (IV) areconverted to the corresponding N-methoxy-N-methyl amides (IX) byreaction of the corresponding acids (IV) with N,O-dimethylhydroxylaminehydrochloride in the presence of a base, such as pyridine, and acoupling reagent, such as dicyclohexylcarbodiimide (DCC) in an organicsolvent, such as methylene chloride at a temperature between 0-50° C.Treatment of intermediates (IX) with Grignard reagents or organolithiumreagents, such as methyl lithium, gives ketones (X). Reduction of thenitro group in intermediates (X) with a reducing agent, such as iron inacetic acid, gives the corresponding amines (XI) which cyclize atelevated temperatures, such as 50-150° C., in the presence of an acid,such as p-toluenesulfonic acid, in an inert organic solvent, such asbenzene, to give compounds of this invention (XII). Alkylation of (XII)with an alkyl halide, such as methyl iodide, or an acyl halide such asacetyl chloride, gives compounds of this invention (XIII). Treatment ofintermediates (X) with a Grignard reagent, such as methylmagnesiumchloride, give tertiary alcohols (XIV). Reduction of the nitro group inintermediates (XIV) with a metal, such as iron, in an acid, such asacetic acid, followed by heating at a temperature from 50-150° C., gives(XV) which are compounds of this invention. Reaction of compounds (XV)with an alkyl halide, such as methyl iodide, or an acyl halide, such asacetyl chloride, gives (XVI) which are compounds of this invention.

[0028] The enantiomerically pure compounds of this invention can beprepared according to the following Scheme 3 from commercially availablestarting materials or starting materials which can be prepared usingliterature procedures. This scheme shows the preparation ofrepresentative (R)-compounds of formula IA of this invention, startingwith the known 2-(R)-piperazinecarboxylic acid (reference below).Starting from the known 2-(S)-piperazinecarboxylic acid gives the(S)-compounds of formula IB of this invention.

[0029] In Scheme 3, the (R)-2-piperazinecarboxylic acid (preparedaccording to the references below) was converted by standard methods tothe N-protected amino-acid (XVII); the symbol Cbz represents acarbobenzyloxy group. A solution of(R)-4-carbobenzyloxypiperazine-2-carboxylic acid (XVII) is allowed toreact with a substituted ortho-nitrofluorobenzene to give a4-carbobenzyloxy-1-(o-nitro-substituted-phenyl)-(R)-piperazine-2-carboxylicacid (XVIII). The reaction is carried out in an inert organic solvent,such as dimethylformamide, in the presence of a base, such astriethylamine, at a temperature above ambient temperature, such as50-70° C.

[0030] The intermediate (XVIII) is cyclized by a process involvingreduction of the nitro group to an amino group, preferably by reactionof a metal, such as iron, in an acid, such as acetic acid, followed byheating at elevated temperature, such as 50-70° C., to effectcyclization to (XIX). Removal of the Cbz protecting group using 30% HBrin acetic acid, boron tribromide, or catalytic reduction, gives chiralproducts of this invention (IA).

[0031] The ability of the compounds of this invention to act as 5HT_(2C)agonists was established is several standard pharmacological testprocedures; the procedures used and results obtained are provided below.

[0032] Test Procedures

[0033] 5HT_(2C) Receptor Binding Test Procedure

[0034] To evaluate high affinity for the 5HT_(2C) receptor, a CHO(Chinese Hamster Ovary) cell line transfected with the cDNA expressingthe human 5-hydroxy-tryptamine_(2C) (h5HT_(2C)) receptor was maintainedin DMEM (Dulbecco's Modified Eagle Media) supplied with fetal calfserum, glutamine, and the markers: guaninephosphoribosyl transferase(GTP) and hypoxanthinethymidine (HT). The cells were allowed to grow toconfluence in large culture dishes with intermediate changes of mediaand splitting. Upon reaching confluence, the cells were harvested byscraping. The harvested cells were suspended in half volume of freshphysiological phosphate buffered saline (PBS) solution and centrifugedat low speed (900×g). This operation was repeated once more. Thecollected cells were then homogenized with a polytron at setting #7 for15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA. Thehomogenate was centrifuged at 900×g for 15 min to remove nuclearparticles and other cell debris. The pellet was discarded and thesupernatant fluid recentrifuged at 40,000×g for 30 min. The resultingpellet was resuspended in a small volume of Tris.HCl buffer and thetissue protein content was determined in aliquots of 10-25 microliter(μl) volumes. Bovine Serum Albumin (BSA) was used as the standard in theprotein determination by the method of Lowry et al., (J. Biol. Chem.,193:265 (1951). The volume of the suspended cell membranes was adjustedwith 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mMpargyline and 4 mM CaCl₂ to give a tissue protein concentration of 1-2mg per ml of suspension. The preparation membrane suspension (many timesconcentrated) was aliquoted in 1 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

[0035] Binding measurements were performed in a 96 well microtiter plateformat, in a total volume of 200 μl. To each well was added: 60 μl ofincubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4mM CaCl₂; 20 μl of [¹²⁵I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).

[0036] The dissociation constant, KD of [¹²⁵I] DOI at the humanserotonin 5HT_(2C) receptor was 0.4 nM by saturation binding withincreasing concentrations of [¹²⁵I] DOI. The reaction was initiated bythe final addition of 100.0 μl of tissue suspension containing 50 μg ofreceptor protein. Nonspecific binding is measured in the presence of 1μM unlabeled DOI added in 20.0 μl volume. Test compounds were added in20.0 ml. The mixture was incubated at room temperature for 60 min. Theincubation was stopped by rapid filtration. The bound ligand-receptorcomplex was filtered off on a 96 well unifilter with a Packard®Filtermate 196 Harvester. The bound complex caught on the filter diskwas dried in a vacuum oven heated to 60° C. and the radioactivitymeasured by liquid scintillation with 40 μl Microscint-20 scintillant ina Packard TopCount® equipped with six (6) photomultiplier detectors.

[0037] Specific binding is defined as the total radioactivity bound lessthe amount bound in the presence of 1 μM unlabeled DOI. Binding in thepresence of varying concentrations of test drugs is expressed as percentof specific binding in the absence of drug. These results are thenplotted as log % bound vs log concentration of test drug. Non linearregression analysis of data points yields both the IC50 and the Kivalues of test compounds with 95% confidence limits. Alternatively, alinear regression line of decline of data points is plotted, from whichthe IC50 value can be read off the curve and the Ki value determined bysolving the following equation: ${Ki} = \frac{IC50}{1 + {L/{KD}}}$

[0038] where L is the concentration of the radioactive ligand used andthe KD is the dissociation constant of the ligand for the receptor, bothexpressed in nM.

[0039] The following Ki's are provided for various reference compounds:

[0040] Ki value and 95% confidence interval. Ritanserin  2.0 (1.3-3.1)nM Ketanserin 94.8 (70.7-127.0) nM Mianserin  2.7 (1.9-3.8) nM Clozapine23.2 (16.0-34.0) nM Methiothepin  4.6 (4.0-6.0) nM Methysergide  6.3(4.6-8.6) nM Loxapine 33.0 (24.0-47.0) nM mCPP  6.5 (4.8-9.0) nM DOI 6.2 (4.9-8.0) nM

[0041] Stimulation of [³H] Inositol Monophosphate Production by 5HT_(2C)Agonists.

[0042] CHO cells transfected with the cDNA expressing the human5-HT_(2C) receptor were cultured in Dulbecco's modified Eagle's medium(DMEM) supplemented with 10% fetal bovine serum and non-essential aminoacids. Upon reaching confluence the cells were harvested using PBS/EDTAand plated in 24 well plates at an initial density of 2.5×10⁵ cells perwell. One (1) ml of maintenance medium containing 1 μCi/ml myo-[³H]inositol was added to each well. After 48 hours labeling, the cells werewashed once with 0.5 ml DMEM containing 25 mM HEPES and 10 mM LiCl, thenpreincubated with the medium for 30 min (antagonists were included inthis period if tested). At the end of the preincubation, the medium wasremoved, the cells were then incubated with test compounds (in presenceof antagonists if needed) for 30 min. The reaction was terminated byremoval of the incubation solution and addition of 0.5 ml ice-cold 5%PCA, followed by 15 to 30 min incubation on ice. 200 μl of 0.5 M Tes/1.5M K₂CO₃ was added to each well to neutralize to pH 7, and plates wereleft on ice for another 15 to 30 min to precipitate all salts. Theliquid and solid phases were separated by centrifugation.

[0043] A portion (350 μl) of the upper aqueous phase was applied toDowex AG-1X8 (formate form, 100-200 mesh) columns. The columns were thenwashed stepwise with 10 ml of water and 10 ml of 25 mM ammonium formateto remove free myo-[³H]inositol and deacylated phosphoinositol,respectively. Finally 10 ml of 0.2 M ammonium formate solution wasapplied to the columns to elute [³H] inositol monophosphate ([³H] IP₁)directly into scintillation vials. Of this eluate, 1 ml was used todetermine radioactivity by scintillation counting.

[0044] Agonist-stimulated levels of [³H]inositol monophosphate (IP₁) isexpressed as a percentage of the response observed with a maximallyeffective concentration of 5-HT (10 μM). A 3-parameter logistic functionis used to generate estimate of EC₅₀/IC₅₀. Antagonists are tested in thepresence of 10 μM 5-HT.

[0045] The following data are provided for various reference compounds:5-HT 15.1 nM EC₅₀ mCPP 46.8 nM EC₅₀   60% E_(MAX) (relative to 5-HT)SB200646  286 nM IC₅₀ (10 μM 5-HT as agonist)

[0046] Effects of Compounds on Feeding Behavior in Rats

[0047] Eight (8) male Sprague-Dawley rats weighing 150-180 g wereseparated into individual cages and acclimated to a powdered diet for 2weeks. During this period and throughout the test procedure, the foodcup and the animals were weighed daily. Following the acclimationperiod, animals were fasted for 24 hours and then injected with eithervehicle or one of 4 doses of the test compound. Food intake was assessedat 2 and 24 hours following compound administration. Compounds to beevaluated were injected 1-2×per week until all animals had received alldoses of the test compound. The order of doses were chosen using to amodified Latin Square design. Additional studies may be conducted insatiated rats at the start of the dark cycle. Compounds were injectedi.p, s.c. or p.o. At the end of the study effects of the test compoundon food intake was evaluated using a repeated measures ANOVA. Data werecollected were 2 hour food intake (g). Data were subjected to one-wayANOVA with posthoc t-tests to assess group differences. Whereappropriate, ED50 values were calculated. The ED50 value is the dosethat produces a 50% reduction in food intake during the test period.

[0048] Results

Results from in vitro Test Procedures

[0049] 5HT_(2C) Affinity 5HT_(2C) Stimulation of DOI/Agonist binding %Emax IP3 Compound (Ki, nM) (5HT, 100%) (EC50, nM) Example 1 4.33 107.5012.00 Example 2 4.18 112.50 7.92 Example 3 66.40 89.00 289.50 Example 41.00 99.00 7.32 Example 5 7.00 100.00 33.80 Example 6 8.00 77.00 23.20Example 7 8.00 100.00 97.30 Example 8 516.00 85.00 2607.00 Example 925.00 100.00 18.80 Example 10 1036.00  ND* ND Example 11 19.79 73% @ 1μM ND Example 12 9.00 95.00 30.00 Example 13 91.00 ND ND

Results from in vivo 5HT_(2C) Food Intake in Rats (24 hr Fast)

[0050] Compound Route of Admin. ED50 (mg/kg) Example 1 ip 1.91 po 9.73Example 2 ip 1.99 Example 11 ip 9.99

[0051] The results obtained in this standard pharmacological testprocedures demonstrate that the compounds of this invention are 5HT_(2C)receptor agonists useful for the treatment of diseases involving thecentral nervous system such as obsessive-compulsive disorder;depression; anxiety; panic disorder; schizophrenia; migraine; sleepdisorders, such as sleep apnea; eating disorders, such as hyperphagia;obesity; type II diabetes; and epilepsy.

[0052] The compounds of this invention can be formulated neat or with apharmaceutical carrier for administration, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmacological practice. Thepharmaceutical carrier may be solid or liquid.

[0053] A solid carrier can include one or more substances which may alsoact as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders, thecarrier is a finely divided solid which is in admixture with the finelydivided active ingredient. In tablets, the active ingredient is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

[0054] Liquid carriers are used in preparing solutions, suspensions,emulsions, syrups, elixirs and pressurized compositions. The activeingredient can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, a mixtureof both or pharmaceutically acceptable oils or fats. The liquid carriercan contain other suitable pharmaceutical additives such assolubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoringagents, suspending agents, thickening agents, colors, viscosityregulators, stabilizers or osmo-regulators. Suitable examples of liquidcarriers for oral and parenteral administration include water (partiallycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,lecithins, and oils (e.g. fractionated coconut oil and arachis oil). Forparenteral administration, the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

[0055] Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compounds of this invention can also beadministered orally either in liquid or solid composition form.

[0056] The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of this invention may be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of this invention may also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier may take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments may be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient may also besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

[0057] The dosage requirements vary with the particular compositionsemployed, the route of administration, the severity of the symptomspresented and the particular subject being treated. Based on the resultsobtained in the standard pharmacological test procedures, projecteddaily dosages of active compound would be 0.02 μg/kg-750 μg/kg.Treatment will generally be initiated with small dosages less than theoptimum dose of the compound. Thereafter the dosage is increased untilthe optimum effect under the circumstances is reached; precise dosagesfor oral, parenteral, nasal, or intrabronchial administration will bedetermined by the administering physician based on experience with theindividual subject treated. Preferably, the pharmaceutical compositionis in unit dosage form, e.g. as tablets or capsules. In such form, thecomposition is sub-divided in unit dose containing appropriatequantities of the active ingredient; the unit dosage forms can bepackaged compositions, for example, packaged powders, vials, ampoules,pre filled syringes or sachets containing liquids. The unit dosage formcan be, for example, a capsule or tablet itself, or it can be theappropriate number of any such compositions in package form.

[0058] The following provides the preparation of a representativecompound of this invention.

EXAMPLE 18,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0059] A. 4-Carbobenzyloxypiperazine-2-Carboxylic Acid, Copper Chelate

[0060] To a solution of 10 g of piperazine-2-carboxylic acid in 40 mL ofH₂O is added 39 mL of 2.5 N NaOH. A solution of 6.5 g of CuSO₄.5H₂O in80 mL of H₂O is then introduced and the resulting deep blue solution iscooled to 0° C. To this cooled solution is added 5 g of solid NaHCO₃ inone portion followed by the dropwise addition of a solution of 7.7 mL ofbenzylchloroformate in 40 mL of dioxane over 10 minutes. The pH ismonitored and NaHCO₃ is added as needed to maintain a basic solution.The ice bath is then removed and the reaction mixture is stirredovernight at ambient temperature. The blue precipitate is filtered andthe solid is washed with cold H₂O (20 mL), EtOH (20 mL), and EtOAc (20mL) to give 10.4 g of a light blue solid.

[0061] B.4-Carbobenzyloxy-1-(4,5-Dichloro-2-Nitrophenyl)Piperazine-2-CarboxylicAcid

[0062] A mixture of 10.4 g of 4-carbobenzyloxypiperazine-2-carboxylicacid, copper chelate and 7.9 g of ethylenediaminetetraacetic acid,disodium salt in 800 mL of H₂O is heated to 80° C. for 3 hours. Aftercooling to room temperature, the mixture is concentrated to dryness. Amixture of this solid, 7.3 g of 1,2-dichloro-4-fluoro-5-nitrobenzene,and 20 mL of triethylamine in 100 mL of dimethylsulfoxide is heated to60° C. for 12 hours. After cooling to ambient temperature, the resultingmixture is treated with HCl to pH 3. The mixture is then diluted withH₂O and extracted with ethyl acetate. The combined extracts are driedover MgSO₄ and concentrated to give 16 g of crude product.

[0063] C.3-Carbobenzyloxy-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0064] A rapidly stirred solution of 16 g of4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)piperazine-2-carboxylicacid in 200 mL of acetic acid is heated to 60° C. and then 16 g of ironpowder is added in portions. The reaction mixture is stirred at 60° C.for 3 hours and then allowed to cool to room temperature. The mixture isdiluted with 1 N HCl and the resulting precipitate is collected. Thesolid is washed with water and ether to give 11 g of product. The crude¹H NMR is consistent. A small amount (1 g) of the product is purified byflash column chromatography (gradient elution with 25% ethylacetate-hexanes to 100% ethyl acetate) to give an analytically puresample.

[0065]¹H NMR (400 MHz, d₆-DMSO) δ10.8 (s, 1H); 7.39-7.31 (m, 5H); 7.04(s, 1H); 6.96 (s, 1H); 5.12 (s, 2H); 4.38 (d, 1H, J=13.0 Hz); 4.06 (d,1H, J=13.1 Hz); 3.71 (d, 1H, J=11.5 Hz); 3.63 (dd, 1H, J=11.2, 3.7 Hz);2.99 (brs, 2H); 2.68 (dt, 1H, J=12.1, 3.6 Hz).

[0066] IR (KBr) 3400, 3250, 2800, 1690, 1500, 1370, 1240, 1130, 860,770, 730 cm⁻¹.

[0067] MS (ESI, m/e (%)) 406 (100, [M+H]⁺), 408 (65, [M+H]⁺).

[0068] Anal. Calc'd for C₁₉H₁₇Cl₂N₃O₃: C, 56.17; H, 4.22; N, 10.34.Found: C, 55.95; H, 3.88; N, 10.29.

[0069] D.8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0070] A solution of 20 g of KOH in 50 mL of H₂O is added to a solutionof 4.2 g of3-carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onein 50 mL of methanol. The resulting reaction mixture is heated to refluxfor 3 hours and then is allowed to cool to ambient temperature. Thesolution is concentrated and the crude solid is partitioned betweenwater and ethyl acetate. The phases are separated and the aqueous phaseis extracted with ethyl acetate. The combined organic phases areconcentrated. The crude solid is dissolved in a minimum amount of hotethanol and then a solution of HCl in ethanol is added to pH 3. Thesolid is collected and dried in a vacuum oven at 80° C. to give 2.4 g ofproduct as its hydrochloride salt.

[0071]¹H NMR (400 MHz, d₆-DMSO) δ11.0 (s, 1H); 9.51 (br s, 2H); 7.12 (s,1H); 7.02 (s, 1H); 4.02 (dd, 1H, J=11.5, 3.4 Hz); 3.88 (d, 1H, J=11.0Hz); 3.61 (m, 1 H); 3.41 (d, 1H, J=9.8 Hz); 3.15-2.98 (m, 3H).

[0072] IR (KBr) 3420, 3200, 3020, 2970, 2800, 1695, 1500, 1460, 1430,1395, 1375, 1290, 1140 cm⁻¹.

[0073] MS (APCI, m/e (%)) 272 (100, [M+H]⁺), 274 (65, [M+H]⁺).

[0074] Anal. Calc'd for C₁₁H₁₂Cl₃N₃O: C, 42.81; H, 3.92; N, 13.62.Found: C, 42.66; H, 3.75; N, 13.33

EXAMPLE 2(R)-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0075] Method A (Separation Method)

[0076] The enantiomers of the compound of Example 1 were separated byHPLC using a Chiracel AD column with 100% ethanol at a flow rate of 0.5mL/min to provide the compounds of Example 2 and 3. The first enantiomer(Example 2) elutes at 10.4 min ([α]²⁵ _(D)+27.8) and the second (Example3) at 13.7 min ([α]²⁵ _(D)−25.5).

[0077] Method B (Chiral Synthesis)

[0078] A. (R)-4-Carbobenzyloxypiperazine-2-Carboxylic Acid.

[0079] To a solution of 5.0 g of (R)-piperazine-2-carboxylic acid¹ in 30mL of water is added 5.0 g CuSO₄.5H₂O dissolved in 60 mL of H₂O. Thesolution is cooled to 0-5° C. and 10.0 g of NaHCO₃ is added followed bythe addition of 5.3 g of benzylchloro-formate in 40 mL of acetone over90 minutes. The mixture is warmed to ambient temperature and stirred for24 h. The blue precipitate is filtered and the solid is washed with coldwater. The solids are slurried in 100 mL of 1:1 methanol: water mixtureand the pH adjusted to <4 by the addition of 2.5 N HCl. The solution isapplied to a column of 400 g of AG 50W-8X resin that had been pre-washedwith a mixture of 1:16:16 pyridine: methanol: water. The product waseluted with the same solvent mixture and the combined product fractionsare concentrated under reduced pressure (<50° C.) to give a semi-solidresidue. This material is slurried with 50 mL of ethanol to obtaincrystalline solid. The solids are collected and dried to give 6.0 g(59.5%) of white solid, mp 246-8° C. decomposed.

[0080] H¹ NMR (400 Hz, d₆-DMSO) δ7.37-7.30 (m, 5H); 5.08 (s, 2H); 4.19(d, 1H, J=12.1 Hz); 3.89 (d, 1H, J=13.8); 3.27 (dd, 1H, J=11.0, 4.0 Hz);3.08 (m, 3H); 2.82 (dt, 1H, J=12.2, 3.6 Hz).

[0081] IR (KBr) 3050, 1700, 1620, 1430, 1400, 1235, 1150 cm⁻¹.

[0082] MS (ESI(+), m/e (%)) 265 (100, [M+H]⁺).

[0083] Anal. Calc'd for C₁₃H₁₆N₂O₄: C, 59.08; H, 6.10; N, 10.60. Found:C, 59.04; H, 6.09; N, 10.40.

[0084] Chiral Purity=99.99% (HPLC: Chiralcel WH, 4.6×25 mm).

[0085] [α]_(D)=−38.77° (c=1, H₂O).

[0086] B.(R)-4-Carbobenzyloxy-1-(4,5-Dichloro-2-Nitrophenyl)-Piperazine-2-CarboxylicAcid.

[0087] To a slurry containing 5.0 g of(R)-4-carbobenzyloxypiperazine-2-carboxylic acid, 4.2 g of1,2-dichloro-fluoro-5-nitrobenzene, 85 mL of water and 170 mL ofdimethylformamide is added slowly 5.3 mL of triethylamine. The solutionis heated to 50° C. for 5 hours, then at ambient temperature overnight.The dark orange solution is concentrated under reduced pressure (1-2 mm,<50° C.) to an orange oily residue. This oil is dissolved in 400 mL ofethyl acetate and washed with 100 mL of 1 N HCl (2×), with 150 mL ofwater (2×), and 100 mL of brine. The organic layer is dried over MgSO₄,filtered and concentrated to give 8.1 g ( 94.2%) of title compound as anorange solid foam.

[0088] MS (ESI(+), m/e (%)) 454 (40, [M+H]⁺), 456 (35, [M+H]⁺), 471(100, [M+NH₄]⁺) and 473 (100, [M+NH₄]⁺).

[0089] Chiral Purity=99.99% (HPLC: Whelk-O, 4.6×250 mm).

[0090] C.(R)-Carbobenzyloxy-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0091] To a solution of 8.0 g(R)-4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)-piperazine-2-carboxylicacid in 200 mL of acetic acid is added 6.0 g of iron powder. With goodstirring, the mixture is heated at 60° C. for 2 hours, followed byconcentrated under reduced pressure (1-2 mm, <40° C.) to a gray-blackresidue. This material was slurried with 400 mL of ethyl acetate andfiltered. This process was repeated. The combined ethyl acetatefiltrates are washed with 150 mL of 1 N HCl, 200 mL of water (2×), 200mL of brine and dried over MgSO₄. Filtration and concentration of thesolvent gave a semi-solid material that is crystallized from ethylacetate-hexane to afford 5.44 g (76.1%) of title compound as a whitesolid, mp 136-138° C.

[0092] H¹ NMR (400 Hz, d₆-DMSO) δ10.81 (s, 1H); 7.38-7.31 (m, 5H); 7.04(s, 1H); 6.95 (s, 1H); 5.11 (s, 2H); 4.37 (d, 1H, J=12.5 Hz); 4.05 (d,1H, J=13.4 Hz); 3.70 (d, 1H, J=11.2 Hz); 3.63 (dd, 1H, J=3.6, 10.8 Hz);3.00 (bs, 2H); 2.66 (dt, 1H, J=3.6, 12.2 Hz).

[0093] IR (KBr) 3240, 1710, 1675, 1500, 1300, 1245, 1130 cm⁻¹.

[0094] MS (APCI, m/e (%)) 406 (100, [M+H]⁺) and 408 (90, [M+H]⁺).

[0095] Anal. Calc'd for C₁₉H₁₇Cl₂N₃O₃: C, 56.17; H, 4.27; N, 10.34.Found: C, 55.97; H, 4.33; N, 9.90.

[0096] Chiral Purity=99.99% (HPLC: Chiralcel AD, 4.6×250 mm).

[0097] [α]_(D)=+23.89° (c=1, CHCl₃).

[0098] D.(R)-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0099] To a solution of 5.0 g of(R)-carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino-[1,2a]quinoxalin-5(6H)-onein 100 mL of acetic acid is added dropwise 15 mL of 30% HBr in aceticacid. The solution is stirred at ambient temperature for 5 hour andconcentrated under reduced pressure (1 mm, <40° C.) to give solidresidue. The residue is dissolved in 300 mL of ethyl acetate and washedwith 100 mL of 1 N NaOH, 200 mL of water (2×) and 300 mL of brine anddried over MgSO₄. Filtration and concentration of the solvent affords3.59 g (99%) of crude free base. Purification by column chromatography(265 g of silica gel, 9:1 ethylacetate: 2M NH₃ in methanol) gives 1.8 g(54.9%) of product as a yellowish solid, mp 203° C. decomposed. Thesolid (1.6 g) was dissolved in 50 mL of methanol and treated with anexcess of 1 M HCl in ether to afford 1.6 g (88.2%) of the hydrochloridesalt as an off-white solid, mp >290° C.

[0100] H¹ NMR (400 Hz, d₆-DMSO) δ11.00 (s, 1H); 9.58 (s,2H); 7.12 (s,1H); 7.02 (s, 1H); 4.03 (dd, 1H, J=11.6, 3.6 Hz); 3.87 (d, 1H, J=10.7Hz); 3.61 (dd, 1H, J=12.9, 2.0 Hz); 3.41 (d, 1H, J=9.5 Hz); 3.42-2.99(m, 3H).

[0101] IR (KBr) 2950, 2700, 1700, 1590, 1500 cm⁻¹.

[0102] MS (APCI, m/e (%)) 272 (100, [M+H]⁺) and 274 (65, [M+H]⁺).

[0103] Anal. Calc'd for C₁₁H₁₁Cl₂N₃O.HCl: C, 42.81; H, 3.92; N, 13.62.Found: C, 42.45; H, 3.78; N, 13.43.

[0104] Chiral Purity=99.99% (HPLC: Chiralcel AD, 4.6×250 mm).

[0105] [α]_(D)=+27.72° (c=1, DMSO).

EXAMPLE 3(S)-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0106] Method A (Separation Method)

[0107] The enantiomers of the compound of Example 1 were separated byHPLC using a Chiracel AD column with 100% ethanol at a flow rate of 0.5mL/min to provide the compounds of Example 2 and 3. The first enantiomer(Example 2) elutes at 10.4 min ([α]²⁵ _(D)+27.8) and the second (Example3) at 13.7 min ([α]²⁵ _(D)−25.5).

[0108] Method B (Chiral Synthesis)

[0109] A. (S)-4-Carbobenzyloxypiperazine-2-Carboxylic Acid.

[0110] To a solution of 4.0 g of (S)-piperazine-2-carboxylic acid¹ in 70mL of water is added 4.2 g of CuCl₂. The pH of the blue solution isadjusted to 10 by the addition of 2.5 N NaOH and 70 mL of acetone isadded. The solution is cooled to 0-5° C. and 5.3 g ofbenzylchloroformate in 40 mL of acetone is added over 90 minutes. The pHis monitored and maintained by the addition of 1 N NaOH. The mixture iswarmed to ambient temperature and stirred overnight. The blueprecipitate is filtered and the solid is washed with cold water. Thesolids are slurried in 100 mL of 1:1 methanol: water mixture and the pHadjusted to <4 by the addition of 2.5 N HCl. The solution is applied toa column of 400 g of AG 50W-8X resin that had been pre-washed with amixture of 1:16:16 pyridine: methanol: water. The product was elutedwith the same solvent mixture and the combined product fractions areconcentrated under reduced pressure (<50° C.) to give a semi-solidresidue. This material is slurried with 50 mL of methanol to obtaincrystalline solids. The solids are collected and dried to give 4.0 g(50%) of white solid, mp 247° C. decomposed.

[0111] H¹ NMR (400 Hz, d₆-DMSO) δ7.37-7.30 (m, 5H); 5.08 (s, 1H); 4.19(d, 1H, J=12.1 Hz); 3.89 (d, 1H, J=13.8); 3.27 (dd, 1H, J=11.0, 4.0 Hz);3.08 (m, 3H); 2.82 (dt, 1H, J=12.2, 3.6 Hz).

[0112] IR (KBr) 3200, 1700, 1620, 1430, 1400, 1235, 1150 cm⁻¹.

[0113] MS (APCI, m/e (%)) 263 (100, [M−H]⁻).

[0114] Anal. Calc'd for C₁₃H₁₆N₂O₄: C, 59.08; H, 6.10; N, 10.60. Found:C, 58.90; H, 6.20; N, 10.58.

[0115] Chiral Purity=99.88% (HPLC: Chiralcel WH, 4.6×25 mm).

[0116] B.(S)-4-Carbobenzyloxy-1-(4,5-Dichloro-2-Nitrophenyl)-Piperazine-2-CarboxylicAcid.

[0117] To a slurry containing 1.5 g of(S)-4-carbobenzyloxypiperazine-2-carboxylic acid, 1.25 g of1,2-dichloro-fluoro-5-nitrobenzene, 25 mL of water and 50 mL ofdimethylformamide is added slowly 1.6 mL of triethylamine. The solutionis heated to 50° C. for 5 hours, then at ambient temperature over night.The dark orange solution is concentrated under reduced pressure (1-2 mm,<50° C.) to an orange oily residue. This oil is dissolved in 100 mL ofethyl acetate and washed with 20 mL of 1 N HCl (2×), with 100 mL ofwater (2×), and 100 mL of brine. The organic layer is dried over MgSO₄,filtered and concentrated to give 2.5 g (99%) an orange solid foam.

[0118] MS (APCI, m/e (%)) 452 (100, [M−H]⁻) and 454 (75, [M−H]⁻).

[0119] Anal. Calc'd for C₁₉H₁₇Cl₂N₃O₆.0.5 H₂O: C, 49.26; H, 3.92; N,9.07. Found: C, 48.90; H, 3.80; N, 8.74.

[0120] Chiral Purity=99.99% (HPLC: Whelk-O, 4.6×250 mm).

[0121] [α]_(D)=−64.2° (c=1, MeOH).

[0122] C.(S)-Carbobenzyloxy-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0123] To a solution of 1.5 g(S)-4-carbobenzyloxy-1-(4,5-dichloro-2-nitrophenyl)-piperazine-2-carboxylicacid in 40 mL of acetic acid is added 1.2 g of iron powder. With goodstirring, the mixture is heated at 60° C. for 2 hours, then concentratedunder reduced pressure (1-2 mm, <40° C.) to a gray-black residue. Thismaterial was slurried with 100 mL of ethyl acetate (2×). The combinedethyl acetate filtrates are washed with 100 mL of 1N HCl, 200 mL ofwater (2×), 100 mL of brine and dried over MgSO₄. Filtration andconcentration of the solvent gave a semi-solid material that iscrystallized from hexane to afford 1.08 g (80.6%) of title compound as awhite solid, mp 174-6° C.

[0124] H¹ NMR (400 Hz, d₆-DMSO) δ10.93 (s, 1H); 7.41-7.31 (m, 5H); 7.04(s, 1H); 6.95 (s, 1H); 5.11 (s, 1H); 4.37 (d, 1H, J=12.5 Hz); 4.05 (d,1H, J=13.4 Hz); 3.70 (d, 1H, J=11.2 Hz); 3.63 (dd, 1H, J=3.6, 10.8 Hz);3.00 (bs, 2H); 2.66 (dt, 1H, J=3.6, 12.2 Hz).

[0125] IR (KBr) 3240, 1710, 1675, 1500, 1300, 1245, 1130 cm⁻¹.

[0126] MS (APCI, m/e (%)) 406 (70, [M+H]⁺) and 408 (45, [M+H]⁺).

[0127] Anal. Calc'd for C₁₉H₁₇Cl₂N₃O₃: C, 56.17; H, 4.27; N, 10.34.Found: C, 56.26; H, 4.18; N, 10.37.

[0128] Chiral Purity=99.9% (HPLC: Chiralcel AD, 4.6×250 mm).

[0129] D.(S)-8,9-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0130] To a solution of 0.155 g of(S)-carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino-[1,2a]quinoxalin-5(6H)-onein 8 mL of acetic acid is added dropwise 1.5 mL of 30% HBr in aceticacid. The solution is stirred at ambient temperature for 2.5 hour andconcentrated under reduced pressure (1 mm, <40° C.) to afford 0.18 g oftan solid. The solids dissolved in 50 mL of ethyl acetate and washedwith 10 mL of 1 N NaOH, 20 mL of water (2×) and 30 mL of brine and driedover MgSO₄. Filtration and concentration of the solvent affords 0.056 g(53.8%) of title compound as a white solid.

[0131] H¹ NMR (400 Hz, d₆-DMSO) δ10.63 (s, 1H); 6.96 (s, 1H); 6.92 (s,1H); 3.49 (bd, 1H, J=10.0 Hz); 3.41 (dd, 1H, J=10.5, 3.5 Hz); 3.29 (m,1H); 2.94 (bd, 1H, J=9.9 Hz) 2.67-2.53 (m, 4H).

[0132] MS (APCI, m/e (%)) 272 (100, [M+H]⁺) and 274 (55, [M+H]⁺).

[0133] Chiral Purity=99.9% (HPLC: Chiralcel AD, 4.6×250 mm).

[0134] [α]_(D)=−25.5° (c=1, DMSO).

EXAMPLE 48,9-Dichloro-2,3,4,4a,5,6-Hexahydro-1H-Pyrazino[1,2-a]Quinoxaline,dihydrochloride

[0135] A solution of 5 mL of 1 M BH₃.THF in THF was added to a cooled(0° C.) solution of 0.43 g of8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onein 20 mL of THF. The resulting solution was allowed to gradually warm toroom temperature overnight. The reaction was quenched with methanol andconcentrated. The crude material was dissolved in methanol and againconcentrated. The product was purified by flash column chromatographythrough silica gel (elution with 40% ethyl acetate-hexanes) to afford0.30 g (73%). The material was dissolved in ethanol and HCl in EtOH wasadded until the solution was acidic. Diethyl ether was then added untila precipitate formed. The solid was collected and dried under vacuum togive 68 mg of product as the dihydrochloride salt.

[0136]¹ H NMR (400 MHz, d₆-DMSO) δ9.44-9.35 (m, 2H); 6.86 (s, 1H); 6.59(s, 1H); 3.78 (d, 1H, J=11.8 Hz); 3.37-3.24 (m, 4H); 3.07-2.89 (m, 3H);2.69 (m, 1H).

[0137] IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450,1380, 1270, 1140, 1110 cm⁻¹.

[0138] MS (APCI, m/e (%)) 258 (100, [M+H]⁺), 260 (65, [M+H]⁺).

EXAMPLE 5(R)-8,9-Dichloro-2,3,4,4a,5,6-Hexahydro-1H-Pyrazino[2-a]Quinoxaline,dihydrochloride

[0139] By the same procedure described for Example 4, 1.8 g of(R)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onewas reduced to give 0.77 g of product.

[0140] The enantiomers were be separated by HPLC using a Chirapak ADcolumn with 100% methanol at a flow rate of 0.8 mL/min. The firstenantiomer eluted at 7.2 min and the second at 8.9 min.

[0141] HPLC analysis indicated an ee of >99% (7.2 min retention time).

[0142]¹H NMR (400 MHz, d₆-DMSO) δ9.44-9.35 (m, 2H); 6.86 (s, 1H); 6.59(s, 1H); 3.78 (d, 1H, J=11.8 Hz); 3.37-3.24 (m, 4 H); 3.07-2.89 (m, 3H);2.69 (m, 1 H).

[0143] IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450,1380, 1270, 1140, 1110 cm⁻¹.

[0144] MS (APCI, m/e (%)) 258 (100, [M+H]⁺), 260 (65, [M+H]⁺).

EXAMPLE 6(S)-8,9-Dichloro-2,3,4,4a,5,6-Hexahydro-1H-Pyrazino[1,2-a]Quinoxaline,dihydrochloride

[0145] By the same procedure described for Example 4, 0.80 g of(S)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onewas reduced to give 0.31 g of product.

[0146] The enantiomers were separated by HPLC using a Chirapak AD columnwith 100% methanol at a flow rate of 0.8 mL/min. The first enantiomereluted at 7.2 min (Example 5) and the second at 8.9 min (Example 6).

[0147] HPLC analysis indicated an ee of >99% (8.9 min retention time).

[0148] [α]²⁵ _(D)+4.35

[0149]¹H NMR (400 MHz, d₆-DMSO) δ9.44-9.35 (m, 2H); 6.86 (s, 1H); 6.59(s, 1H); 3.78 (d, 1H, J=11.8 Hz); 3.37-3.24 (m, 4 H); 3.07-2.89 (m, 3H);2.69 (m, 1H).

[0150] IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450,1380, 1270, 1140, 1110 cm⁻¹.

[0151] MS (APCI, m/e (%)) 258 (100, [M+H]⁺), 260 (65, [M+H]⁺).

[0152] Anal. Calc'd for C₁₁H₁₄Cl₃N₃: C, 44.85; H, 4.79; N, 14.26 Found:C, 44.48; H, 4.84; N, 13.71

EXAMPLE 79-Chloro-8-Trifluoromethyl-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0153] A.4-Carbobenzyloxy-1-(5-Chloro-2-Nitrophenyl-4-Trifluoromethyl)Piperazine-2-CarboxylicAcid

[0154] A mixture of 0.98 g of 4-carbobenzyloxypiperazine-2-carboxylicacid, 1.0 g of 2,4-dichloro-5-nitrobenzotrifluoride, and 0.99 mL ofdiisopropylethylamine in 35 mL of dimethylsulfoxide is heated to 60° C.for 72 hours. After cooling to ambient temperature, the resultingmixture is treated with HCl to pH 3. The mixture is then diluted withH₂O and extracted with ethyl acetate. The combined extracts are driedover MgSO₄ and concentrated to give the crude product.

[0155] B.3-Carbobenzyloxy-9-Chloro-8-Trifluoromethyl-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0156] Iron powder, 0.64 g, was added in portions to a rapidly stirredsolution of 1.8 g of4-carbobenzyloxy-1-(5-chloro-2-nitrophenyl-4-trifluoromethyl)-piperazine-2-carboxylicacid in 35 mL glacial acetic acid at 50° C. The resulting mixture wasstirred overnight at 50° C. After cooling to ambient temperature, thereaction mixture was poured into 20 mL of H₂O and filtered. The solidwas washed with 1 N HCl and diethyl ether to give 0.59 g of the desiredproduct as a brown solid.

[0157] C.9-Chloro-8-Trifluoromethyl-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0158] A mixture of 0.58 g of3-carbobenzyloxy-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-oneand 2.3 g of potassium hydroxide in 12 mL of 50% aqueous methanol washeated to reflux for 2 h. The reaction mixture was concentrated underreduced pressure to approximately half its original volume. The crudematerial was diluted with 100 mL of ethyl acetate and 100 mL ofsaturated aqueous sodium bicarbonate. The phases were separated and theaqueous phase was extracted with ethyl acetate. The combined organicphases were dried over MgSO₄, filtered, and concentrated. The crudematerial was dissolved in ethanol and a solution of HCl in ethanol wasadded until acidic.

[0159] The resulting mixture was filtered and the solid was washed withether. The solid was then dried in a vacuum oven to give 0.21 g (48%) ofthe desired product as its hydrochloride salt.

[0160]¹H NMR (400 MHz, d₆-DMSO) δ11.0 (s, 1H); 9.47 (br s, 2H); 7.22 (s,1H); 7.18 (s, 1H); 4.19 (dd, 1H, J=11.6, 3.2 Hz); 4.01 (d, 1H, J=11.8Hz); 3.62 (d, 1 H, J=11.7 Hz); 3.41 (d, 1H, J=10.1 Hz); 3.14-3.01 (m,3H).

[0161] IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450,1400, 1370, 1300, 1230, 1160, 1110 cm⁻¹.

[0162] MS (APCI, m/e 306 (100, [M+H]⁺), 308 (33, [M+H]⁺).

[0163] Anal. Calc'd for C₁₂H₁₂ClF₃N₃O: C, 42.13; H, 3.54; N, 12.28.Found: C, 41.88; H, 3.71; N, 11.81.

[0164] The enantiomers were separated by HPLC using a Chirapak AD columnwith 85:15 methanol:water (+0.1% diethylamine) at a flow rate of 0.5mL/min. The first enantiomer (Example 9) eluted at 17.5 min ([α]²⁵_(D)+43) and the second (Example 8) at 22.0 min ([α]²⁵ _(D)-40).

EXAMPLE 8(S)-9-Chloro-8-Trifluoromethyl-2,3,4,4a-Tetrahydro-1H-Pyrazino1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0165] The enantiomers were separated by HPLC using a Chirapak AD columnwith 85:15 methanol:water (+0.1% diethylamine) at a flow rate of 0.5mL/min. The first enantiomer (Example 9) eluted at 17.5 min ([α]²⁵_(D)+43) and the second (Example 8) at 22.0 min ([α]²⁵ _(D)-40).

[0166]¹H NMR (400 MHz, d₆-DMSO) δ11.0 (s, 1H); 9.47 (br s, 2H); 7.22 (s,1H); 7.18 (s, 1H); 4.19 (dd, 1H, J=11.6, 3.2 Hz); 4.01 (d, 1H, J=11.8Hz); 3.62 (d, 1 H, J=11.7 Hz); 3.41 (d, 1H, J=10.1 Hz); 3.14-3.01 (m,3H).

[0167] IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450,1400, 1370, 1300, 1230, 1160, 1110 cm⁻¹.

[0168] MS (APCI, m/e 306 (100, [M+H]⁺), 308 (33, [M+H]⁺).

[0169] [α]²⁵ _(D)−40

[0170] Anal. Calc'd for C₁₂H₁₂ClF₃N₃O: C, 42.13; H, 3.54; N, 12.28.Found: C, 41.59; H, 3.61; N, 12.07.

EXAMPLE 9(R)-9-Chloro-8-Trifluoromethyl-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0171] The enantiomers were separated by HPLC using a Chirapak AD columnwith 85:15 methanol:water (+0.1% diethylamine) at a flow rate of 0.5mL/min. The first enantiomer (Example 9) eluted at 17.5 min ([α]²⁵_(D)+43) and the second (Example 8) at 22.0 min ([α]²⁵ _(D)−40).

[0172] HPLC analysis indicated an ee of 96% (17.5 min retention time).

[0173] [α]²⁵ _(D)+43

[0174]¹H NMR (400 MHz, d₆-DMSO) δ11.0 (s, 1H); 9.47 (br s, 2H); 7.22 (s,1H); 7.18 (s, 1H); 4.19 (dd, 1H, J=11.6, 3.2 Hz); 4.01 (d, 1H, J=11.8Hz); 3.62 (d, 1 H, J=11.7 Hz); 3.41 (d, 1H, J=10.1 Hz); 3.14-3.01 (m,3H).

[0175] IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450,1400, 1370, 1300, 1230, 1160, 1110 cm⁻¹.

[0176] MS (APCI, m/e 306 (100, [M+H]⁺), 308 (33, [M+H]⁺).

[0177] Anal. Calc'd for C₁₂H₁₂ClF₃N₃O: C, 42.13; H, 3.54; N, 12.28.Found: C, 41.83; H, 3.49; N, 12.01.

9,10-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One.Hydrochloride

[0178] A.4-Carbobenzyloxy-1-(5,6-Dichloro-2-Nitrophenyl)Piperazine-2-CarboxylicAcid

[0179] By the same procedure described for Example 7 A, from 0.86 g of2,3,4-trichloro-nitro-benzene and 1.0 g of4-carbobenzyloxypiperazine-2-carboxylic acid, there was obtained 0.75 gof the desired product as a brown oil.

[0180] B.3-Carbobenzyloxy-9,10-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0181] By the same procedure described for Example 7 B, from 0.75 g of4-carbobenzyloxy-1-(5,6-dichloro-2-nitrophenyl)piperazine-2-carboxylicacid and 0.28 g of iron powder, there was obtained 0.34 g (49%) of thedesired product as a brown solid.

[0182] C.9,10-Dichloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0183] By the same procedure described for Example 7, from 0.34 g of4-carbo-benzyloxy-1-(5,6-dichloro-2-nitrophenyl)piperazine-2-carboxylicacid and 1.5 g of potassium hydroxide, there was obtained 18 mg ofproduct isolated as its hydrochloride salt.

[0184]¹H NMR (400 MHz, d₆-DMSO) δ11.1 (s, 1H); 9.05 (br s, 2H); 7.45 (d,1H, J=8.8 Hz); 6.97 (d, 1H, J=8.8 Hz); 4.06 (d, 1H, J=3.7 Hz); 3.84 (d,1H, J=13.2 Hz); 3.29-3.12 (m, 4H); 2.77 (m, 1H).

[0185] IR (KBr) 3440, 3160, 3020, 2970, 1695, 1570, 1470, 1390, 1280cm⁻¹.

[0186] MS (EI, m/e (%) 271 (55, M⁺), 273 (35, M⁺).

[0187] Anal. Calc'd for C₁₁H₁₂Cl₃N₃O: C, 42.81; H, 3.92; N, 13.62.Found: C, 42.40; H, 3.98; N, 12.82.

EXAMPLE 117,9-Dichloro-2,3,4,4A-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One,Hydrochloride

[0188] The title compound was synthesized according to the method ofExample 1, substituting 2,4-dichloro-6-fluoronitrobenzene [Clark, J. H.;Nightengale, D. J. J. Fluorine Chem. (1996) 78 (1), 91-93.] for1,2-dichloro-4-fluoro-5-nitrobenzene. The melting point of the titlecompound is 308-311° C.

EXAMPLE 12(R)-9-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One

[0189] A.(R)-4-Carbobenzyloxy-1-(5-Chloro-2-Nitrophenyl)-Piperazine-2-CarboxylicAcid.

[0190] By the same procedure described for example 2 method 2B, from0.95 g of (R)-4-carbobenzyloxypiperazine-2-carboxylic acid, there wasobtained 1.2 g (85.7%) of title compound as a orange solid, mp 145-155°C.

[0191] MS (ESI, m/e (%)) 420 (100, [M+H]⁺) and 422 (40, [M+H]⁺).

[0192] [α]_(D)=+196.0° (c=1, MeOH).

[0193] B.(R)-Carbobenzyloxy-9-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0194] By the same procedure described for example 2 method 2C, from1.12 g(R)-4-carbobenzyloxy-1-(5-chloro-2-nitrophenyl)-piperazine-2-carboxylicacid, there was obtained 0.80 g (80.8%) of title compound as a whitesolid, mp 139-141° C.

[0195] H¹ (NMR (400 Hz, d₆-DMSO) δ10.73 (s, 1H); 7.38-7.30 (m, 5H);6.87-6.78 (m, 3H); 5.11 (s, 2H); 4.38 (d, 1H, J=13.0 Hz); 4.06 (d, 1H,J=13.0 Hz); 3.70 (d, 1H, J=11.4 Hz); 3.57 (dd, 1H, J=11.0, 3.7 Hz); 2.97(bs, 2H); 2.65 (dt, 1H, J=11.3, 3.5 Hz).

[0196] MS (APCI, m/e (%)) 372 (100, [M+H]⁺) and 374 (40, [M+H]⁺).

[0197] Anal. Calc'd for C₁₉H₁₈ClN₃O₃: C,61.38; H,4.88; N, 11.30. Found:C, 61.46; H, 4.76; N, 11.27.

[0198] C.(R)-9-Chloro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2a]Quinoxalin-5(6H)-One.

[0199] By the same procedure described for example 2 method 2D, from0.50 g(R)-carbobenzyloxy-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]-quinoxalin-5(6H)-one,there was obtained 0.27 g (87.1%) of title compound as a white solid, mp146-149° C.

[0200] MS ((+)ESI, m/e (%)) 238 (85, [M+H]⁺).

[0201] Anal. Calc'd for C₁₁H₁₂ClN₃O: C, 55.59; H, 5.09; N, 17.68. Found:C, 55.59; H, 4.98; N, 17.40.

[0202] [α]²⁵ _(D)=+28.9° (c=1, MeOH).

[0203] Chiral Purity=99.9% (Chiralpak AD, 4.6×250 mm).

[0204] The hydrochloride salt was prepared from HCl and MeOH as a lightgreen solid, mp decomposed 270-280° C.

[0205] H¹ NMR (400 Hz, d₆-DMSO) δ10.90 (s, 1H); 9.53 (s,2H); 6.94 (bs,1H); 6.90-6.84 (m, 2H); 3.96 (dd, 1H, J=13.1, 3.4 Hz); 3.86 (d, 1H,J=11.0 Hz); 3.62 (bd, 1H, J=12.0 Hz); 3.42 (d, 1H, J=10.6 Hz); 3.10-2.97(m, 3H).

[0206] MS (APCI, m/e (%)) 238 (100, [M+H]⁺) and 240 (40, [M+H]⁺).

[0207] Anal. Calc'd for C₁₁H₁₂ClN₃O.HCl: C, 48.19; H, 4.78; N, 15.33.Found: C,48.38; H, 5.06; N, 14.91.

[0208] Chiral Purity=99.9% (Chiralpak AD, 4.6×250 mm).

[0209] [α]_(D)=+7.0° (c=1, MeOH).

EXAMPLE 13 8,9-Difluoro-2,3,4,4a-Tetrahydro-1H- Pyrazino[12-a]Quinoxalin-5(6H)-One

[0210] A.4-Carbobenzyloxy-1-(4,5-Difluoro-2-Nitrophenyl)-Piperazine-2-CarboxylicAcid.

[0211] By the same procedure described for example 2 method 2B, from 1.5g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and1,2,4-trifluoro-5-nitrobenzene, there was obtained 0.4 g (16.7%) oftitle compound as an orange-red residue.

[0212] MS (APCI, m/e (%)) 422 (45, [M+H]⁺).

[0213] B.3-Carbobenzyloxy-8,9-Difluoro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One.

[0214] By the same procedure described for example 2 method 2C, from0.29 g of4-carbobenzyloxy-1-(4,5-difluoro-2-nitrophenyl)-piperazine-2-carboxylicacid, there was obtained 0.17 g (66.0%) of title compound as a whitesolid, mp 226-8° C.

[0215] H¹ NMR (400 MHz, d₆-DMSO) δ10.70 (s, 1H); 7.39-7.30 (m, 5H);6.98-6.92 (m, 1H); 6.82-6.77 (m, 1H); 5.11 (s, 2H); 4.38 (d, 1H, J=13.0Hz); 4.06 (d, 1H, J=13.0 Hz); 3.62 (d, 1H, J=11.0 Hz); 3.52 (dd, 1H,J=11.0, 4.0 Hz); 2.98 (bs, 2H); 2.65 (dt, 1H, J=11.0, 4.0 Hz).

[0216] MS (APCI, m/e (%)) 374 (100, [M+H]⁺).

[0217] Anal. Calc'd for C₁₉H₁₇F₂N₃O₃: C, 61.12; H, 4.59; N, 11.25.Found: C, 60.79; H, 4.54; N, 10.95.

[0218] C.8,9-Difluoro-2,3,4,4a-Tetrahydro-1H-Pyrazino[1,2-a]Quinoxalin-5(6H)-One

[0219] By the same procedure described for example 2 method 2D, from0.28 g3-carbobenzyloxy-8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-onethere was obtained 0.14 g (78.1%) of title compound as a white solid.The hydrochloride salt of this material, prepared from an excess ofhydrogen chloride in ethanol, was obtained as a white solid, mp >280° C.

[0220] H¹ NMR (400 MHz, d₆-DMSO) δ10.89 (s, 1H); 9.57 (s, 2H); 7.07-7.02(m, 1H); 6.90-6.86 (m, 1H); 3.93 (dd, 1H, J=11.0, 3.0 Hz); 3.77 (d, 1H,J=11.0 Hz); 3.62 (m, 1H); 3.62 (m, 1H); 3.42 (d, 1H, J=10.0 Hz);3.10-2.95 (m, 3H).

[0221] MS ((+)APCI, m/e (%)) 240 (75, [M+H]⁺).

[0222] Anal. Calc'd for C₁₁H₁₁F₂N₃O: C, 47.92; H, 4.39; N, 15.24. Found:C, 47.96; H, 4.37; N, 14.86.

What is claimed:
 1. A method of treating depression in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 2. The method of claim 1, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl.
 3. The method of claim 1 wherein the compound is selected from the formulae:

R is hydrogen or alkyl of 1-6 carbon atoms; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 4. The method of claim 3, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl.
 5. The method of claim 1 wherein the compound is selected from: a) 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; b) 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; c) (R)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; d) (R)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; e) (S)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; f) (S)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; g) 8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline or a pharmaceutically acceptable salt thereof; h) 8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline dihydrochloride salt; i) (R)-8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline or a pharmaceutically acceptable salt thereof; j) (R)-8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline dihydrochloride salt; k) (S)-8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline or a pharmaceutically acceptable salt thereof; l) (S)-8,9-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline dihydrochloride salt; m) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; n) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; o) (S)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; p) (S)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; q) (R)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; r) (R)-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; s) 9,10-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; t) 9,10-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one hydrochloride salt; u) 7,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; v) 7,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt; w) (R)-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; x) (R)-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one hydrochloride salt; y) 8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one or a pharmaceutically acceptable salt thereof; or z) 8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one hydrochloride salt.
 6. The method of claim 1 wherein the mammal is a human.
 7. A method of treating anxiety, obsessive-compulsive disorder, or panic disorder in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 8. The method of claim 7, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety.
 9. A method of treating migraines in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 10. The method of claim 9, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety.
 11. A method of treating eating disorders in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 12. The method of claim 11, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety.
 13. A method of treating type II diabetes in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 14. The method of claim 13, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety.
 15. A method of treating epilepsy in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R¹ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 16. The method of claim 15, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety.
 17. A method of treating sleep disorders in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I having the structure

R is hydrogen or alkyl of 1-6 carbon atoms; R′ is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl; X is CR₅R₆ or a carbonyl group; R₅ and R₆ are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R₁, R₂, R₃, or R₄ are not hydrogen.
 18. The method of claim 17, wherein the non-hydrogen substituents of R₁, R₂, R₃, or R₄ are halogen or trifluoromethyl and X is a carbonyl moiety. 